1. Field of the Technology
The invention relates to a method for preparing tetrahydrobiopterin and related compounds and analogs of biopterin. More specifically, it relates to a stereoselective process for preparing 5,6,7,8-tetrahydro-6-(L-erythro-1′,2′-dihydroxypropyl)pterin and includes the conversion of 6-(L-erythro-1,2,3-trihydroxypropyl)pterin and/or 6-substituted pterins to tetrahydrobiopterin.
2. Brief Description of Related Technology
Tetrahydrobiopterin is a biogenic amine of the naturally-occurring pterin family. Pterins are present in physiological fluids and tissues in reduced and oxidized forms, however, only the 5,6,7,8-tetrahydrobiopterin is biologically active. Tetrahydrobiopterin is a chiral molecule, and the 6R enantiomer, and 1′R,2′S,6R diastereomer of the tetrahydrobiopterin is the known biologically active form. The synthesis and disorders of tetrahydrobiopterin are described in Blau et al., Disorders of tetrahydrobiopterin and related biogenic amines, in Scriver C R, Beaudet A L, Sly W S, Valle D, Childs B, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th ed., New York: McGraw-Hill, 2001, at pages 1275-1776.
In a living body tetrahydrobiopterin plays a very important role as cofactor of essential enzymes (e.g., the aromatic amino acid hydroxylases, the nitric oxide synthetases, as a coenzyme in a catecholamine-serotonin synthesis.) Tetrahydrobiopterin is an indispensable compound for biosynthesis of the neurotransmitters dopamine and hydroxytyptamine, of noradrenalin, adrenaline, and melatonin. The importance of tetrahydrobiopterin has been recognized in the course of the fundamental studies thereon. A deficiency of tetrahydrobiopterin causes serious neurological disorders like phenylketonuria (PKU) and Parkinson's disease. Symptoms due to such diseases can be remarkably improved by administration of tetrahydrobiopterin. Further, it has been recognized that tetrahydrobiopterin is effective for curing infantile autism and depressions.
Such useful pharmacological activities, as well as the challenging chemical structures of the molecule, have stimulated many synthetic efforts directed toward the preparation of tetrahydrobiopterin. For example, tetrahydrobiopterin has been prepared by: (1) the reaction of 4-hydroxy-2,5,6-triaminopyrimidine (TAP) and 5-deoxy-L-arabinose as described in E. L. Patterson et al., J. Am. Chem. Soc., 78, 5868 (1956); (2) the reaction of TAP and 5-deoxy-L-arabinose phenylhydrazone, as described in Matsuura et al., Bull. Chem. Soc. Jpn., 48, 3767 (1975); (3) the reaction of TAP and triacetyloxy-5-deoxy-L-arabinose phenylhydrazone, as described in M. Viscontini et al., Helv. Chim. Acta., 60, 211 (1977); (4) the reaction of oxime and benzyl α-aminocyanoacetate and condensation of the resulting 3-(1,2-dihydroxypropyl)-pyrazine-1-oxide derivatives with guanidine followed by deoxygenation of the N-oxide, as described in E. C. Taylor et al., J. Am. Chem. Soc., 96, 6781 (1974); (5) the reaction of α-hydroxyketone (prepared from crotonic acid) and TAP, as described in M. Viscontini et al., Helv. Chim. Acta., 55, 574 (1972); and (6) the reaction of TAP having protected hydroxyl group and 4-acetoxy-2,3-epoxypentanal followed by oxidation with iodine and deprotection, as described in Matsuura et al., Chemistry of Organic Synthesis, Vol. 46, No. 6, p. 570 (1988), by protecting the hydroxyl group of S-alkyl lactate with a trityl group, reducing the resulting alkyl 2-trityloxypropionate to (S)-2-trityloxypropanol, oxidizing it to (S)-2-trityloxypropanal, treating it with a 2-furyl metal compound to form (1S,2S)-1-(2-furyl)-2-trityloxy-1-propanal followed by oxidation and hydrolysis to form 2,3-dideoxy-6-trityloxyhepto-2-enopyranose-4-ulose, reducing it to 6-trityloxyhepto-2-ene-1,4,5-triol, acylating it to from 1,4,5-triacyloxy-6-trityloxyhepto-2-ene followed by oxidation to afford 2,3 diacyloxy-4-hydroxy-1-pentanal, treating it with phenylhydrazine to from a hydrazine, and condensing the hydrazine with a 3,5,6-triaminopyrimidinol followed by oxidation and deacylation, as described in Japanese Kokai No. 221380/1989.
Each of these conventional processes for preparing tetrahydrobiopterin have several drawbacks, including, for example, expensive and sparsely available carbohydrates are required as starting material to provide the asymmetric carbon atom at its side-chain, in that yield and purity are low due to multi-reaction steps, unstable intermediates are generated that require troublesome treatment operations, and troublesome purification procedures are required.
The prior processes for preparing tetrahydrobiopterin starting from 5-deoxy-L-arabinose are economically disadvantageous, since 5-deoxy-L-arabinose of the required purity is only not readily available in large quantities. Also the product from the reactions involving 5-deoxy-L-arabinose is known to undergo degradation. Other prior preparation of tetrahydrobiopterin have the disadvantage that biopterin is produced in a DL-form and optical resolution is required for obtaining the desired L-biopterin, thus leading to complicated process step and low yield. Indeed, in A. Kaiser, H. P. Wessel, Helv. Chim. Acta, Vol. 70, p. 766, 1987, states at page 768, that “These results and considerations demonstrate that no high-yield synthesis of biopterin from neopterin can be expected due to pyrrolo-pteridin formation upon activation of the side-chain terminus of neopterin.”
Therefore, the conventional processes are unsuitable for industrial production of the compound and its derivatives. There exists a need for a process for the preparation of tetrahydrobiopterin, and analogs thereof in good yield using inexpensive starting material. A need also exists for an industrial scale process for the preparation of substantially optically pure tetrahydrobiopterin with an improved yield and a high stereoselectivity.